Project Summary Despite decades of research, effective treatment for Alzheimer?s disease remains elusive. Drugs developed so far treat the symptoms rather than the underlying disease. Recent advances in neural stimulation via electric, magnetic, or optogenetic tools have demonstrated cognition improvement in animal models and in preliminary clinical studies. These techniques, however, are invasive, deliver nonspecific stimulation, and/or depend on introducing foreign genes, tempering their clinical impact. Our currently funded R21 BRAIN Initiative study is focused on developing piezoelectric nanoparticles for noninvasive ultrasound neural stimulation. The goal of the grant is to target barium titanate nanoparticles (BTNPs) to the axon initial segment of neurons. Then, focused ultrasound energy is used to generate a charge on the surface of the BTNPs and open voltage-gated ion channels. The end goal of the original project is to create a versatile technique which can be used to probe neural circuits in vivo. In this administrative supplement proposal, we seek to extend the concept to treating Alzheimer?s disease. We hypothesize that by specifically stimulating cholinergic neurons, the progression of the disease could be halted or even reversed. This supplement is meant to initiate these studies and to begin the shift towards Alzheimer?s disease. Specifically, we will develop a new variant of BTNPs which are targeted specifically to cholinergic neurons via attachment of acetylcholine receptor antibodies. In vitro studies of cultured rat hippocampal neurons will confirm binding of the BTNPs and establish the ability to stimulate neurons noninvasively with ultrasound. These results will be directly compared to the studies currently underway targeting the axon initial segment. At the conclusion of these experiments, we will be poised to initiate in vivo studies in a mouse model of Alzheimer?s disease.